Novel nannocystin A analogues as anticancer therapeutics: Synthesis, biological evaluations and structure-activity relationship studies

Eur J Med Chem. 2019 May 15:170:99-111. doi: 10.1016/j.ejmech.2019.03.011.

Qiang Liu ¹, Xiaohong Yang ¹, Jie Ji ¹, Shao-Lin Zhang ², Yun He ³

Affiliations

1 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
2 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: zhangsl@cqu.edu.cn.
3 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: yun.he@cqu.edu.cn.

PMID: 30878835 DOI: 10.1016/j.ejmech.2019.03.011

Abstract

Nannocystin A is a novel 21-membered macrocyclic lactam that targets eukaryotic translation elongation factor 1α (eEF1A) and displays potent antiproliferative activities. Herein, a series of nannocystin A analogues were synthesized and their structure-activity relationship (SAR) were established based on the MTT assay and western blotting analysis. The SAR enabled us to identify a structurally simplified nannocystin A analogue LQ18, which exhibited potent antiproliferative activities with IC₅₀ values ranging from 4.3 to 48 nM against the tested cell lines, and inhibited eEF1A1 expression in A549 cell line. LQ18 arrested cell cycle at G2 phase and induced A549 cell Apoptosis via up-regulation of Caspase-3, caspase-9 and Bax protein expressions in a dose-dependent manner, while it significantly decreased the Bcl-2 expression. Collectively, these data demonstrated that LQ18 could be a promising lead for the development of structurally novel eEF1A1 inhibitor for Cancer treatment.

Keywords

Anticancer; Nannocystin a; SAR study.

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